Idiopathic pulmonary fibrosis (IPF), the most common of the interstitial lung diseases, occurs in about 128,000 people, with 48,000 new cases diagnosed annually in the US. The typical clinical course is a progressive fibrotic disease characterized by scarring and `honeycombing' of the lungs causing an irreversible loss of the tissue's ability to transport oxygen. Co-morbid pulmonary hypertension is commonly seen in patients with IPF and contributes to a worsening clinical prognosis. IPF ultimately robs a patient of the ability to breathe leading to a mortality rate of 66% at five years following diagnosis. This high death rate corresponds to an unappreciated large number of fatalities per year (n=40,000), about the same yearly rate as deaths due to breast cancer. Current treatments have mainly focused on blocking proliferation of lung fibroblasts. A novel target?Protease-Activated Receptor-2 (PAR2)?has recently been identified as an important mediator in the pathogenesis of IPF. PAR2 is a cell surface receptor that is upregulated in reactive lung epithelium, fibroblasts, and inflammatory cells during progression of IPF, and IPF patients with high expression of PAR2 in the lung have worse survival and clinical indices. Increased pro-coagulant protease (factors VIIa/Xa/TF) activity in the lung, and local inflammatory proteases such as mast cell tryptase trigger aberrant PAR2 signaling and activation of the fibrotic response. The goal of this Oasis fast-track STTR proposal is based on our discovery of a PAR2 inhibitor, OA-235c, as a potent suppressor of aberrant lung fibrotic processes. The cell-penetrating, lipidated inhibitor OA-235c, was developed using our proprietary Pepducin? technology. Pepducin? technology offers a unique opportunity to target the intracellular surface of recalcitrant G-protein coupled receptors (GPCRs) such as PAR2 with exquisite specificity, potency and long half-lives, with prolonged drug exposure to the target tissue, namely lung. In pre-clinical studies, we show that OA-235c significantly suppresses fibrosis and inflammation in IPF and other fibrotic-organ models. In preliminary toxicology studies, OA-235c was safe and tolerated in dogs, rats, and mice with no evidence of pancreas, liver, heart, kidney, lung, bone marrow, or other organ toxicity or any laboratory abnormalities at high multiples of the therapeutic dose. Oasis Pharmaceuticals successfully preformulated and produced OA-235c at 98% purity and high chemical and proteolytic stability. Phase 1 (Aim 1) will identify and validate a formulation at 50-100 mg/mL solubility for OA-235c and demonstrate significant suppression of lung fibrosis and determine any drug-drug interactions with the two standard-of-care IPF agents. The goal of Phase 2 (Aim 2) will be to complete the IND Data Package under GLP conditions with GMP OA-235c with submission of the IND to the FDA as the final milestone. Rapid completion of the proposed preclinical and IND-enabling studies would generate a novel drug candidate with an anti-fibrotic mode of action for the potential treatment of IPF in patients.